Cell-Cycle Kinases Coordinate the Resolution of Recombination Intermediates with Chromosome Segregation

Homologous recombination leads to the formation of DNA joint molecules (JMs) that must be resolved to allow chromosome segregation, but how resolution is temporally coupled with chromosome segregation is unknown. Here, we have analyzed the role of the cell-cycle kinases Cdk and Cdc5 in coordinating these events through their involvement in the phosphoregulation of the Mus81-Mms4 nuclease. By identifying CDC5 and MMS4 mutants that uncouple Mus81-Mms4 activation from cell-cycle progression, we show that JM disengagement, prior to anaphase initiation, safeguards chromosome segregation. By simultaneously stimulating the cleavage of cohesin and activating Mus81-Mms4 at the G2/M transition, Cdk and Cdc5 coordinate the sequential elimination of all chromosomal interactions in preparation for chromosome segregation. Conversely, untimely Cdc5 expression increases crossover frequency due to premature activation of Mus81-Mms4. Therefore, temporal restriction of JM resolution, imposed by Cdk/Cdc5, minimizes the potential for loss of heterozygosity while preventing chromosome missegregation and aneuploidy. [Display omitted] •Cdk and Cdc5 coordinate DNA repair with chromosome segregation•Activation of Mus81-Mms4 is required for efficient DNA repair and chromosome segregation•Joint molecule resolution is required for timely anaphase initiation•Misregulated expression of Cdc5 causes increased mitotic crossover frequency The disengagement of DNA joint molecules (JMs) generated during the repair of DNA lesions is required for chromosome segregation. Now, West and colleagues show that the cell-cycle kinases Cdc28/CDK and Cdc5/PLK1, which regulate cohesin cleavage, also promote JM processing by activating the structure-selective nuclease Mus81-Mms4. The coupling of nuclease activation to cell-cycle progression prevents the toxic actions of Mus81-Mms4 during the S phase and coordinates the timely elimination of all types of chromosomal interactions in preparation for anaphase initiation.